EP4396193A1 - Analogues de n-acétylgalactosamine fonctionnalisés - Google Patents
Analogues de n-acétylgalactosamine fonctionnalisésInfo
- Publication number
- EP4396193A1 EP4396193A1 EP22865693.0A EP22865693A EP4396193A1 EP 4396193 A1 EP4396193 A1 EP 4396193A1 EP 22865693 A EP22865693 A EP 22865693A EP 4396193 A1 EP4396193 A1 EP 4396193A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- compound
- alkyl
- independently
- optionally substituted
- unsubstituted
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- OVRNDRQMDRJTHS-CBQIKETKSA-N N-Acetyl-D-Galactosamine Chemical class CC(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@H](O)[C@@H]1O OVRNDRQMDRJTHS-CBQIKETKSA-N 0.000 title abstract description 7
- 108091034117 Oligonucleotide Proteins 0.000 claims abstract description 45
- 238000000034 method Methods 0.000 claims abstract description 26
- 150000001875 compounds Chemical class 0.000 claims description 176
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 107
- -1 (4-methoxyphenyl)diphenylmethyl Chemical group 0.000 claims description 96
- 125000004432 carbon atom Chemical group C* 0.000 claims description 74
- 125000004474 heteroalkylene group Chemical group 0.000 claims description 49
- 239000007787 solid Substances 0.000 claims description 48
- 125000002947 alkylene group Chemical group 0.000 claims description 46
- 125000006239 protecting group Chemical group 0.000 claims description 45
- 229910052757 nitrogen Inorganic materials 0.000 claims description 44
- 150000003839 salts Chemical class 0.000 claims description 43
- 229910052739 hydrogen Inorganic materials 0.000 claims description 42
- 239000001257 hydrogen Substances 0.000 claims description 42
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 35
- 238000006243 chemical reaction Methods 0.000 claims description 30
- 229910052760 oxygen Inorganic materials 0.000 claims description 29
- 150000002431 hydrogen Chemical group 0.000 claims description 27
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 25
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 23
- 229910052717 sulfur Inorganic materials 0.000 claims description 18
- 125000002103 4,4'-dimethoxytriphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)(C1=C([H])C([H])=C(OC([H])([H])[H])C([H])=C1[H])C1=C([H])C([H])=C(OC([H])([H])[H])C([H])=C1[H] 0.000 claims description 16
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 13
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 11
- SXADIBFZNXBEGI-UHFFFAOYSA-N phosphoramidous acid Chemical group NP(O)O SXADIBFZNXBEGI-UHFFFAOYSA-N 0.000 claims description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 9
- 125000006586 (C3-C10) cycloalkylene group Chemical group 0.000 claims description 8
- 125000006585 (C6-C10) arylene group Chemical group 0.000 claims description 8
- 125000005647 linker group Chemical group 0.000 claims description 8
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 claims description 7
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 6
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 5
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 abstract description 18
- 239000003814 drug Substances 0.000 abstract description 4
- 125000000524 functional group Chemical group 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 131
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 105
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 98
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 89
- 239000000203 mixture Substances 0.000 description 74
- 125000000217 alkyl group Chemical group 0.000 description 48
- OVRNDRQMDRJTHS-KEWYIRBNSA-N N-acetyl-D-galactosamine Chemical compound CC(=O)N[C@H]1C(O)O[C@H](CO)[C@H](O)[C@@H]1O OVRNDRQMDRJTHS-KEWYIRBNSA-N 0.000 description 41
- 239000005289 controlled pore glass Substances 0.000 description 41
- 125000000623 heterocyclic group Chemical group 0.000 description 39
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 38
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 36
- 125000004429 atom Chemical group 0.000 description 35
- 229910052799 carbon Inorganic materials 0.000 description 35
- 125000005842 heteroatom Chemical group 0.000 description 31
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 30
- 125000003118 aryl group Chemical group 0.000 description 29
- 239000012044 organic layer Substances 0.000 description 29
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 28
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 27
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 26
- 239000011541 reaction mixture Substances 0.000 description 26
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 25
- MBLBDJOUHNCFQT-UHFFFAOYSA-N N-acetyl-D-galactosamine Natural products CC(=O)NC(C=O)C(O)C(O)C(O)CO MBLBDJOUHNCFQT-UHFFFAOYSA-N 0.000 description 23
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 22
- 229910052938 sodium sulfate Inorganic materials 0.000 description 22
- 125000000753 cycloalkyl group Chemical group 0.000 description 21
- 125000001072 heteroaryl group Chemical group 0.000 description 21
- 125000001424 substituent group Chemical group 0.000 description 19
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 18
- 239000007832 Na2SO4 Substances 0.000 description 18
- 238000000746 purification Methods 0.000 description 18
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 17
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 description 17
- 239000000243 solution Substances 0.000 description 17
- 239000002585 base Substances 0.000 description 16
- 239000012267 brine Substances 0.000 description 16
- 238000001914 filtration Methods 0.000 description 16
- 239000000463 material Substances 0.000 description 16
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 16
- 239000012043 crude product Substances 0.000 description 14
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 14
- 150000008300 phosphoramidites Chemical class 0.000 description 13
- 125000003342 alkenyl group Chemical group 0.000 description 12
- 125000000304 alkynyl group Chemical group 0.000 description 12
- 125000004452 carbocyclyl group Chemical group 0.000 description 12
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 12
- 239000012074 organic phase Substances 0.000 description 12
- 235000011152 sodium sulphate Nutrition 0.000 description 12
- 238000004128 high performance liquid chromatography Methods 0.000 description 11
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 11
- 239000011734 sodium Substances 0.000 description 11
- 238000005406 washing Methods 0.000 description 11
- 125000004737 (C1-C6) haloalkoxy group Chemical group 0.000 description 10
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 10
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 10
- 125000003545 alkoxy group Chemical group 0.000 description 10
- 125000005843 halogen group Chemical group 0.000 description 10
- 238000005859 coupling reaction Methods 0.000 description 9
- 125000004122 cyclic group Chemical group 0.000 description 9
- 239000002777 nucleoside Substances 0.000 description 9
- 230000003647 oxidation Effects 0.000 description 9
- 238000007254 oxidation reaction Methods 0.000 description 9
- MCTWTZJPVLRJOU-UHFFFAOYSA-N 1-methyl-1H-imidazole Chemical compound CN1C=CN=C1 MCTWTZJPVLRJOU-UHFFFAOYSA-N 0.000 description 8
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
- 125000003710 aryl alkyl group Chemical group 0.000 description 8
- 230000008878 coupling Effects 0.000 description 8
- 238000010168 coupling process Methods 0.000 description 8
- 238000011068 loading method Methods 0.000 description 8
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 8
- 238000002515 oligonucleotide synthesis Methods 0.000 description 8
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 8
- 238000003556 assay Methods 0.000 description 7
- 229910052736 halogen Inorganic materials 0.000 description 7
- 150000002367 halogens Chemical class 0.000 description 7
- 235000000346 sugar Nutrition 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- FALRKNHUBBKYCC-UHFFFAOYSA-N 2-(chloromethyl)pyridine-3-carbonitrile Chemical compound ClCC1=NC=CC=C1C#N FALRKNHUBBKYCC-UHFFFAOYSA-N 0.000 description 6
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 6
- 102000005427 Asialoglycoprotein Receptor Human genes 0.000 description 6
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 6
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 6
- 125000005631 S-sulfonamido group Chemical group 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 125000004450 alkenylene group Chemical group 0.000 description 6
- 108010006523 asialoglycoprotein receptor Proteins 0.000 description 6
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 150000001721 carbon Chemical group 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 238000006642 detritylation reaction Methods 0.000 description 6
- 239000006260 foam Substances 0.000 description 6
- 125000001188 haloalkyl group Chemical group 0.000 description 6
- 239000011630 iodine Substances 0.000 description 6
- 229910052740 iodine Inorganic materials 0.000 description 6
- 150000003833 nucleoside derivatives Chemical class 0.000 description 6
- 125000003729 nucleotide group Chemical group 0.000 description 6
- 125000003003 spiro group Chemical group 0.000 description 6
- 229940014800 succinic anhydride Drugs 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- 239000007821 HATU Substances 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 239000008346 aqueous phase Substances 0.000 description 5
- 238000010511 deprotection reaction Methods 0.000 description 5
- 125000001183 hydrocarbyl group Chemical group 0.000 description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 description 5
- 239000007790 solid phase Substances 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 125000004646 sulfenyl group Chemical group S(*)* 0.000 description 5
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 4
- STBLNCCBQMHSRC-BATDWUPUSA-N (2s)-n-[(3s,4s)-5-acetyl-7-cyano-4-methyl-1-[(2-methylnaphthalen-1-yl)methyl]-2-oxo-3,4-dihydro-1,5-benzodiazepin-3-yl]-2-(methylamino)propanamide Chemical compound O=C1[C@@H](NC(=O)[C@H](C)NC)[C@H](C)N(C(C)=O)C2=CC(C#N)=CC=C2N1CC1=C(C)C=CC2=CC=CC=C12 STBLNCCBQMHSRC-BATDWUPUSA-N 0.000 description 4
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 4
- KJUGUADJHNHALS-UHFFFAOYSA-N 1H-tetrazole Chemical compound C=1N=NNN=1 KJUGUADJHNHALS-UHFFFAOYSA-N 0.000 description 4
- VKIGAWAEXPTIOL-UHFFFAOYSA-N 2-hydroxyhexanenitrile Chemical compound CCCCC(O)C#N VKIGAWAEXPTIOL-UHFFFAOYSA-N 0.000 description 4
- 238000004679 31P NMR spectroscopy Methods 0.000 description 4
- OIVLITBTBDPEFK-UHFFFAOYSA-N 5,6-dihydrouracil Chemical compound O=C1CCNC(=O)N1 OIVLITBTBDPEFK-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 4
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- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 description 4
- 229910019142 PO4 Inorganic materials 0.000 description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- 239000004793 Polystyrene Substances 0.000 description 4
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 4
- 239000012317 TBTU Substances 0.000 description 4
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 4
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 4
- CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 description 4
- 125000004419 alkynylene group Chemical group 0.000 description 4
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- LFSXCDWNBUNEEM-UHFFFAOYSA-N phthalazine Chemical compound C1=NN=CC2=CC=CC=C21 LFSXCDWNBUNEEM-UHFFFAOYSA-N 0.000 description 1
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- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
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- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- OSFBJERFMQCEQY-UHFFFAOYSA-N propylidene Chemical compound [CH]CC OSFBJERFMQCEQY-UHFFFAOYSA-N 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- CPNGPNLZQNNVQM-UHFFFAOYSA-N pteridine Chemical compound N1=CN=CC2=NC=CN=C21 CPNGPNLZQNNVQM-UHFFFAOYSA-N 0.000 description 1
- IGFXRKMLLMBKSA-UHFFFAOYSA-N purine Chemical compound N1=C[N]C2=NC=NC2=C1 IGFXRKMLLMBKSA-UHFFFAOYSA-N 0.000 description 1
- USPWKWBDZOARPV-UHFFFAOYSA-N pyrazolidine Chemical compound C1CNNC1 USPWKWBDZOARPV-UHFFFAOYSA-N 0.000 description 1
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- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
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- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
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- 102000005962 receptors Human genes 0.000 description 1
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- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
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- 239000011780 sodium chloride Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- LBJQKYPPYSCCBH-UHFFFAOYSA-N spiro[3.3]heptane Chemical group C1CCC21CCC2 LBJQKYPPYSCCBH-UHFFFAOYSA-N 0.000 description 1
- CTDQAGUNKPRERK-UHFFFAOYSA-N spirodecane Chemical compound C1CCCC21CCCCC2 CTDQAGUNKPRERK-UHFFFAOYSA-N 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
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- 230000000638 stimulation Effects 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 229960002317 succinimide Drugs 0.000 description 1
- 150000003871 sulfonates Chemical class 0.000 description 1
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- 239000011975 tartaric acid Substances 0.000 description 1
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- 229960001367 tartaric acid Drugs 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- KPXODPHVWBQJEG-UHFFFAOYSA-N tert-butyl 3-[2-amino-3-[3-[(2-methylpropan-2-yl)oxy]-3-oxopropoxy]-2-[[3-[(2-methylpropan-2-yl)oxy]-3-oxopropoxy]methyl]propoxy]propanoate Chemical compound CC(C)(C)OC(=O)CCOCC(N)(COCCC(=O)OC(C)(C)C)COCCC(=O)OC(C)(C)C KPXODPHVWBQJEG-UHFFFAOYSA-N 0.000 description 1
- 229960004559 theobromine Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 description 1
- CBDKQYKMCICBOF-UHFFFAOYSA-N thiazoline Chemical compound C1CN=CS1 CBDKQYKMCICBOF-UHFFFAOYSA-N 0.000 description 1
- VOVUARRWDCVURC-UHFFFAOYSA-N thiirane Chemical compound C1CS1 VOVUARRWDCVURC-UHFFFAOYSA-N 0.000 description 1
- 125000000858 thiocyanato group Chemical group *SC#N 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- RYYWUUFWQRZTIU-UHFFFAOYSA-K thiophosphate Chemical compound [O-]P([O-])([O-])=S RYYWUUFWQRZTIU-UHFFFAOYSA-K 0.000 description 1
- 125000000464 thioxo group Chemical group S=* 0.000 description 1
- 125000005490 tosylate group Chemical group 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- 125000005039 triarylmethyl group Chemical group 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- ZIBGPFATKBEMQZ-UHFFFAOYSA-N triethylene glycol Chemical compound OCCOCCOCCO ZIBGPFATKBEMQZ-UHFFFAOYSA-N 0.000 description 1
- 125000004952 trihaloalkoxy group Chemical group 0.000 description 1
- 125000004385 trihaloalkyl group Chemical group 0.000 description 1
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 239000001226 triphosphate Substances 0.000 description 1
- 235000011178 triphosphate Nutrition 0.000 description 1
- UNXRWKVEANCORM-UHFFFAOYSA-N triphosphoric acid Chemical compound OP(O)(=O)OP(O)(=O)OP(O)(O)=O UNXRWKVEANCORM-UHFFFAOYSA-N 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 229940116269 uric acid Drugs 0.000 description 1
- MSRILKIQRXUYCT-UHFFFAOYSA-M valproate semisodium Chemical compound [Na+].CCCC(C(O)=O)CCC.CCCC(C([O-])=O)CCC MSRILKIQRXUYCT-UHFFFAOYSA-M 0.000 description 1
- 229960000604 valproic acid Drugs 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 229940075420 xanthine Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/18—Acyclic radicals, substituted by carbocyclic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/06—Pyrimidine radicals
- C07H19/067—Pyrimidine radicals with ribosyl as the saccharide radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/06—Pyrimidine radicals
- C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
- C07H21/02—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids with ribosyl as saccharide radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
- C07H21/04—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids with deoxyribosyl as saccharide radical
Definitions
- the present application relates to functionalized N-acetylgalactosamine analogs and their methods of preparation. More specifically, the present application relates to compounds having N-acetylgalactosamine moieties conjugated to a moiety having multiple functional groups using a variety of linkers.
- the functionalized N-acetylgalactosamine analogs disclosed herein may be used for targeted in vivo delivery of oligonucleotide-based therapeutics.
- REFERENCE TO SEQUENCE LISTING [0002] The present application is being filed along with a Sequence Listing in electronic format.
- ASGPR consists of two homologous subunits, designated H1 and H2 in the human system, which form a non-covalent heterooligomeric complex with estimated ratios of 2:1 and 5:1, respectively.
- Both subunits are single-spanning membrane proteins with a calcium-dependent Gal/GalNAc recognition domain (CRDs). On the native receptor on the hepatocyte surface these binding sites are 25-30 ⁇ apart. All conjugations of mono-, di-, tri-, or tetra-GalNAc sugars can enhance the delivery efficiency of oligonucleotides to hepatocytes. Binding hierarchy of polyvalent ligands is : tetraantennary > triantennary >>diantennary >> monoantennary.
- compounds of Formula (II) have the structure of Formula (IIa): or a pharmaceutically acceptable salt thereof.
- compounds of Formula (II) have the structure of Formula (IIb):
- a further aspect of the present disclosure relates to a solid support comprising a compound described herein of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIc) or (IId) covalently attached thereto via R 6 .
- the compound is covalently attached to the solid support via a moiety: wherein the dashed line refers to the connection with the solid support, optionally through an additional linker, and wherein the squiggly line refers to the point of the attachment of the oxygen atom that covalently attached to R 6 of the compound, to the remaining portion of the compound.
- Additional aspect of the present disclosure relates to a method of preparing a synthetic oligonucleotide, comprising reacting a compound described herein of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIc) or (IId) with an oligonucleotide.
- the oligonucleotide may have a 1 to 100 nucleobase length.
- the reaction may be conducted on a solid support.
- DETAILED DESCRIPTION [0016] The compounds disclosed herein relate to novel functionalized GalNAc analogs to provide novel methods for oligonucleotide delivery.
- the functionalized GalNAc analogs disclosed herein may contain a phosphoramidite moiety that allows for the incorporation of the GalNAc analogs to the 5’ end or any internal position of an oligonucleotide.
- the functionalized GalNAc analogs disclosed herein may contain a succinate moiety that allows for the incorporation of the GalNAc analogs on a solid support, which can introduce GalNAc analogs described herein to the 3’ end of oligonucleotide.
- any “R” group(s) represent substituents that can be attached to the indicated atom.
- An R group may be substituted or unsubstituted. If two “R” groups are described as being “taken together” the R groups and the atoms they are attached to can form a cycloalkyl, aryl, heteroaryl, or heterocycle.
- R a and R b and the atom to which it is attached, are indicated to be “taken together” or “joined together” it means that they are covalently bonded to one another to form a ring:
- R a and R b and the atom to which it is attached, are indicated to be “taken together” or “joined together” it means that they are covalently bonded to one another to form a ring:
- substituent may be selected from one or more of the indicated substituents.
- the indicated “optionally substituted” or “substituted” group may be one or more group(s) individually and independently selected from alkyl (e.g., C 1 -C 6 alkyl); alkenyl (e.g., C 2 -C 6 alkenyl); alkynyl (e.g., C 2 -C 6 alkynyl); C 3 -C 8 carbocyclyl (for example, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkenyl, or C 3 -C 8 cyclalkynyl, each may further be optionally substituted, for example, with halo, C 1 -C 6 alkyl, C 1 - C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, (C 1 -C 6 alkoxy)C 1 -C 6 alkyl, or -O(C 1 -C 6 alkyl, or -O
- C a to C b or “C a to b ” in which “a” and “b” are integers refer to the number of carbon atoms in an alkyl group, or the number of ring atoms of a cycloalkyl, aryl, heteroaryl or heterocyclyl group. That is, the alkyl, ring of the cycloalkyl, and ring of the aryl, can contain from “a” to “b”, inclusive, carbon atoms. Likewise, the ring of the heteroaryl and ring of the heterocyclyl can contain from “a” to “b”, inclusive, total ring atoms.
- a “C1 to C4 alkyl” group refers to all alkyl groups having from 1 to 4 carbons, that is, CH3-, CH3CH2- , CH 3 CH 2 CH 2 -, (CH 3 ) 2 CH-, CH 3 CH 2 CH 2 CH 2 -, CH 3 CH 2 CH(CH 3 )- and (CH 3 ) 3 C-;
- a C 3 to C 4 cycloalkyl group refers to all cycloalkyl groups having from 3 to 4 carbon atoms, that is, cyclopropyl and cyclobutyl.
- C 1 -C 6 alkyl includes C 1 , C 2 , C 3 ,C 4 , C 5 and C 6 alkyl, C 2 -C 6 alkyl, C 1 -C 3 alkyl, etc.
- C 3 -C 8 carbocyclyl or cycloalkyl each includes hydrocarbon ring containing 3, 4, 5, 6, 7 and 8 carbon atoms, or a range defined by any of the two numbers, such as C 3 -C 7 cycloalkyl or C 5 -C 6 cycloalkyl.
- alkyl refers to a straight or branched hydrocarbon chain that comprises a fully saturated (no double or triple bonds) hydrocarbon group.
- the alkyl group of the compounds may be designated as “C 1 -C 4 alkyl” or similar designations.
- “C 1 -C 4 alkyl” indicates that there are one to four carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl.
- alkyl groups include, but are in no way limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl (straight chain or branched), and hexyl (straight chain or branched).
- the alkyl group may be substituted or unsubstituted.
- alkenyl refers to a straight or branched hydrocarbon chain containing one or more double bonds. The alkenyl group may have 2 to 20 carbon atoms.
- alkenyl groups include, but are in no way limited to, ethenyl, propenyl, butenyl, pentenyl, and hexenyl, and the like.
- the alkenyl group may be substituted or unsubstituted.
- alkynyl refers to a straight or branched hydrocarbon chain containing one or more triple bonds.
- the alkynyl group may have 2 to 20 carbon atoms.
- C 2 -C 4 alkynyl indicates that there are two to six carbon atoms in the alkynyl chain, i.e., the alkynyl chain is selected from the group consisting of ethynyl, propyn-1-yl, propyn- 2-yl, butyn-1-yl, butyn-3-yl, butyn-4-yl, and 2-butynyl.
- Typical alkynyl groups include, but are in no way limited to, ethynyl, propynyl, butynyl, pentynyl, and hexynyl, and the like.
- alkynyl group may be substituted or unsubstituted.
- cycloalkyl refers to a completely saturated (no double or triple bonds) mono- or multi- cyclic hydrocarbon ring system. When composed of two or more rings, the rings may be joined together in a fused, bridged or spiro fashion.
- fused refers to two rings which have two atoms and one bond in common.
- bridged cycloalkyl refers to compounds wherein the cycloalkyl contains a linkage of one or more atoms connecting non-adjacent atoms.
- bicyclic fused cycloalkyl groups are decahydronaphthalenyl, dodecahydro-1H-phenalenyl and tetradecahydroanthracenyl; examples of bicyclic bridged cycloalkyl groups are bicyclo[1.1.1]pentyl, adamantanyl and norbornanyl; and examples of bicyclic spiro cycloalkyl groups include spiro[3.3]heptane and spiro[4.5]decane. [0029] As used herein, “carbocyclyl” refers to a non-aromatic a mono- or multi- cyclic hydrocarbon ring system.
- aryl group can be a C6 aryl group, or a C 10 aryl group.
- aryl groups include, but are not limited to, benzene and naphthalene.
- An aryl group may be substituted or unsubstituted.
- heteroaryl refers to a monocyclic or multicyclic aromatic ring system (a ring system with fully delocalized pi-electron system) that contain(s) one or more heteroatoms (for example, 1, 2 or 3 heteroatoms), that is, an element other than carbon, including but not limited to, nitrogen, oxygen and sulfur.
- heteroaryl includes fused ring systems where two rings, such as at least one aryl ring and at least one heteroaryl ring or at least two heteroaryl rings, share at least one chemical bond.
- heteroaryl rings include, but are not limited to, furan, furazan, thiophene, benzothiophene, phthalazine, pyrrole, oxazole, benzoxazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, thiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, benzothiazole, imidazole, benzimidazole, indole, indazole, pyrazole, benzopyrazole, isoxazole, benzoisoxazole, isothiazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine,
- heteroaryl group may be substituted or unsubstituted.
- heterocyclyl refers to three-, four-, five-, six-, seven-, eight-, nine-, and ten-membered monocyclic, bicyclic and tricyclic ring system wherein carbon atoms together with from 1 to 5 heteroatoms constitute said ring system.
- a heterocycle may optionally contain one or more unsaturated bonds situated in such a way, however, that a fully delocalized pi-electron system does not occur throughout all the rings (i.e., heterocyclyl groups are not aromatic).
- the heteroatom(s) is an element other than carbon including, but not limited to, oxygen, sulfur and nitrogen.
- Heterocyclyl groups can be linked to the rest of the molecule via a carbon atom in the heterocyclyl group (C- linked) or by a heteroatom in the heterocyclyl group, such as a nitrogen atom (N-linked). Heterocyclyl groups may be unsubstituted or substituted.
- spiro heterocyclyl groups examples include 2-azaspiro[3.3]heptane, 2-oxaspiro[3.3]heptane, 2-oxa-6-azaspiro[3.3]heptane, 2,6-diazaspiro[3.3]heptane, 2- oxaspiro[3.4]octane and 2-azaspiro[3.4]octane.
- alkylene refers to a branched, or straight chain fully saturated di-radical chemical group containing only carbon and hydrogen that is attached to the rest of the molecule via two points of attachment.
- alkylene is an unsubstituted straight chain containing 1, 2, 3, 4, 5, or 6 methylene unit(s).
- (heterocyclyl)alkyl refer to a heterocyclic or a heterocyclyl group, as defined above, connected, as a substituent, via an alkylene group, as defined above.
- the alkylene and heterocyclyl groups of a (heterocyclyl)alkyl may be substituted or unsubstituted. Examples include but are not limited to (tetrahydro-2H-pyran-4-yl)methyl, (piperidin-4-yl)ethyl, (piperidin-4-yl)propyl, (tetrahydro-2H-thiopyran-4-yl)methyl, and (1,3-thiazinan-4-yl)methyl.
- the alkylene is an unsubstituted straight chain containing 1, 2, 3, 4, 5, or 6 methylene unit(s).
- haloalkyl refers to an alkoxy group in which one or more of the hydrogen atoms are replaced by a halogen (e.g., mono-haloalkoxy, di-haloalkoxy and tri- haloalkoxy).
- An O-carboxy may be substituted or unsubstituted.
- a “trihalomethanesulfonyl” group refers to an “X3CSO2-“group wherein X is a halogen.
- a “trihalomethanesulfonamido” group refers to an “X3CS(O)2N(R)-” group wherein X is a halogen and R is hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, aryl, heteroaryl, heterocyclyl, aralkyl, or heterocyclyl(alkyl), as defined herein.
- a “mercapto” group refers to an “-SH” group.
- N-sulfonamido refers to a “RSO2N(RA)-“ group in which R and R A can be independently hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, aryl, heteroaryl, heterocyclyl, aralkyl, or heterocyclyl(alkyl), as defined herein.
- R and R A can be independently hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, aryl, heteroaryl, heterocyclyl, aralkyl, or heterocyclyl(alkyl), as defined herein.
- An N-sulfonamido may be substituted or unsubstituted.
- Each chemical element as represented in a compound structure may include any isotope of said element.
- a hydrogen atom may be explicitly disclosed or understood to be present in the compound.
- the hydrogen atom can be any isotope of hydrogen, including but not limited to hydrogen- 1 (protium), hydrogen-2 (deuterium), and hydrogen-3 (tritium).
- hydrogen- 1 protium
- hydrogen-2 deuterium
- tritium tritium
- Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and may be formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, or the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol.
- the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.
- Other forms in which the compounds of preferred embodiments can be provided include amorphous forms, milled forms and nano- particulate forms.
- Trivalent GalNAc Analogs of Formula (II) [0095] Some embodiments provide a compound of Formula (II), or a pharmaceutically acceptable salt thereof as described herein:
- R 7 is an amino protecting group, e.g., a Cbz group.
- R Z is H.
- R Z is C1-4 alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, or t-butyl.
- L 5 may comprise 3 to 15 membered heteroalkylene comprising 1-5 units of PEG (i.e., L 5 is –(CH2CH2O)–1-5).
- R 5 is a trityl type hydroxy protecting group.
- R 5 is (4- methoxyphenyl)diphenylmethyl (i.e., monomethoxytrityl (MMTr)).
- MMTr monomethoxytrityl
- R 5 is bis(4-methoxyphenyl)phenylmethyl (i.e., 4,4’-dimethoxytrityl (DMTr)).
- R 5 is tris(4-methoxyphenyl)methyl (i.e., 4,4’,4”-trimethoxytrityl (TMTr)). In further embodiments, R 5 is 9-phenylxanthen-9-yl or 9-(4-methoxyphenyl)xanthen-9-yl. [0102] In some embodiments of the compounds of Formula (II), (IIa), (IIb) or (IIIc), R 6 is hydrogen. In other embodiments, R 6 is a phosphoramidite moiety.
- Step 2 Coupling [0113] A 0.02–0.2M solution of nucleoside phosphoramidite (or a mixture of several phosphoramidites) in acetonitrile is activated by a 0.2–0.7 M solution of an acidic azole catalyst, 1H-tetrazole, 5-ethylthio-1H-tetrazole, 2-benzylthiotetrazole, 4,5-dicyanoimidazole, or a number of similar compounds.
- the mixing is usually very brief and occurs in fluid lines of oligonucleotide synthesizers (see below) while the components are being delivered to the reactors containing solid support.
- the activated phosphoramidite in 1.5 – 20-fold excess over the support-bound material is then brought in contact with the starting solid support (first coupling) or a support-bound oligonucleotide precursor (following couplings) whose 5'-hydroxy group reacts with the activated phosphoramidite moiety of the incoming nucleoside phosphoramidite to form a phosphite triester linkage.
- the reaction is also highly sensitive to the presence of water, particularly when dilute solutions of phosphoramidites are used, and is commonly carried out in anhydrous acetonitrile.
- Step 3 Capping [0114]
- the capping step is performed by treating the solid support-bound material with a mixture of acetic anhydride and 1-methylimidazole or, less often, DMAP as catalysts and, in the phosphoramidite method, serves two purposes.
- a small percentage of the solid support-bound 5'-OH groups (0.1 to 1%) remains unreacted and needs to be permanently blocked from further chain elongation to prevent the formation of oligonucleotides with an internal base deletion commonly referred to as (n-1) shortmers.
- the unreacted 5'-hydroxy groups are, to a large extent, acetylated by the capping mixture.
- Step 4 Oxidation [0115]
- the newly formed tricoordinated phosphite triester linkage is not natural and is of limited stability under the conditions of oligonucleotide synthesis.
- the treatment of the support-bound material with iodine and water in the presence of a weak base (pyridine, lutidine, or collidine) oxidizes the phosphite triester into a tetracoordinated phosphate triester, a protected precursor of the naturally occurring phosphate diester internucleosidic linkage.
- a weak base pyridine, lutidine, or collidine
- the solid support is contained in columns whose dimensions depend on the scale of synthesis and may vary between 0.05 mL and several liters.
- the oligonucleotide is released from the solid support and is eluted from the column or the well.
- the two most often used solid-phase materials are controlled pore glass (CPG) and macroporous polystyrene (MPPS).
- CPG controlled pore glass
- MPPS macroporous polystyrene
- CPG is commonly defined by its pore size. In oligonucleotide chemistry, pore sizes of 500, 1000, 1500, 2000, and 3000 ⁇ are used to allow the preparation of about 50, 80, 100, 150, and 200-mer oligonucleotides, respectively.
- the surface of the material is treated with (3-aminopropyl)triethoxysilane to give aminopropyl CPG.
- the aminopropyl arm may be further extended to result in long chain aminoalkyl (LCAA) CPG. The amino group is then used as an anchoring point for linkers suitable for oligonucleotide synthesis.
- LCAA long chain aminoalkyl
- Step 1 GalNAc (10 g, 25.7 mmol) and Compound 1 (15.4 g, 102.7 mmol) were dissolved in DCM (100 mL) and CF 3 SO 3 H (0.34 mL, 3.85 mmol) was then added. The reaction mixture was reflux under argon overnight and then cooled down to rt. This mixture was then poured into 1 M NaHCO3 (51 mL), and the organic layer was separated, washed with water, brine and dried over Na s SO 4 . After filtration, the organic layer was concentrated to dryness under vacuum.
- Compound 20 Compound 18 (1.64 g, 3.48 mmol) was dissolved in DCE (37 mL), and TEA (2.2 mL) was added followed by HATU (5.29 g, 13.9 mmol). This solution was allowed to stir at room temperature for 1 h. A solution of Compound 19 in DCE (37 mL) and TEA (2.2 mL) was added to the activated acid solution. This reaction mixture was stirred at room temperature overnight. Water (100 mL) was added to the reaction mixture with vigorous stirring. The organic phase was separated, and the aqueous phase was extracted with DCM (2 x 50 mL).
- the CPG was washed with THF (50 mL x 3), 10% pyridine in EtOH (50 mL x 3), EtOH (50 mL x 3), acetonitrile (50 mL x 3) and MTBE (50 mL x 3) successively.
- the CPG was dried under reduced pressure overnight to give the compound 34 (21 g, Loading was determined by standard DMTr assay by UV-Vis (498 nm) to be 54 ⁇ mol/g). Ninhydrin test: negative.
- Example 7 Preparation of monovalent GalNAc analogs Compounds 40 and 41 Scheme 7.
- Compound 36 In a 50 mL round bottom flask, oxalyl chloride (0.64 g, 5.0 mmol) was dissolved in DCM (10 mL) at -78 o C under argon atmosphere. DMSO (078 g, 10.01 mmol) was added dropwise. The mixture was stirred at -78 o C for 20 minutes. Compound 35 in DCM (4.0 mL) was added dropwise, the mixture was stirred at -78 o C for 15 minutes, and then Et3N (2.02 g) was added dropwise, the mixture was stirred at -78 o C for 60 minutes.
- the standard synthetic cycle useful in assembling oligonucleotides comprise the steps of: (a) detritylation of the solid phase-bound material; (b) coupling of nucleoside phosphoramidite building block required by the sequence to the solid support-bound material in the presence of coupling agent; (c) capping of unreacted solid support-bound hydroxy groups with a mixture of acetic anhydride and N-methyl imidazole and (d) oxidation of the solid support- bound phosphite triester groups.
- the cycle appropriate for the assembly of the desired oligonucleotide was repeated as required by the sequence in preparation.
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Abstract
Des modes de réalisation de la présente invention concernent des analogues de N-acétylgalactosamine fonctionnalisés, leurs procédés de fabrication et leurs utilisations. En particulier, des analogues de N-acétylgalactosamine monovalents ou trivalents peuvent être préparés en utilisant une grande diversité de lieurs contenant des groupes fonctionnels. Ces analogues de N-acétylgalactosamine fonctionnalisés peuvent être utilisés dans la préparation d'une administration ciblée d'agents thérapeutiques à base d'oligonucléotides.
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